Biological research for the community: legal and ethical perspectives.

Biological Research for the Community: Legal and Ethical Perspectives IRVING LADIMER Immunization through public programs for communities at large, or for specially vulnerable populations, represents one of the most potent health measures offered by governments to pro- tect their people. Far more, they also help resi- dents of other countries, since individuals who are vaccinated serve on behalf of others as well as themselves. National and international co- operation in this area is therefore essential for the advancement of the health and welfare of mankind. In the research, production, and application of vaccines and biologic products for general use, prevention of unfavorable consequences and protection of all participants must be an integral part of the process. In addition to measures to minimize human adverse reactions, consistent with scientific requirements and other means to limit risk and hazard, there must be provision for appropriate restoration and fair compensation for any person affected adversely by association with vaccination. This concern applies to all aspects of vaccine development and use whether directed to scientific exploration, testing, clinical treatment of individuals, or prevention and control of dis- ease. And this concern applies to all individuals who may be involved. he urgency of this con- cern comes from increasing litigation and re- sulting doubt in the public mind regarding the safety of biologic and other medical products. These companion trends may lead to a decline in production of biologics for mass immuniza- tion and a decline in community participation (I). Since it is now known that vaccines carry a certain inherent risk of adverse reaction (in- cluding some serous injuries and deaths), which may be distributed evenly, although minimally, throughout the population, affirmative protec- tion must be devised in advance to meet such contingencies (2). Public health use of certain biologics is clearly distinguishable from individual diagnosis and treatment. Standard biologicals are preven- tive agents, employed for control of com- municable disease, first by safeguarding specific individuals who are immunized and, at the same time, protecting groups. Although vaccinations suggest analogies to other community preventive medical measures such as fluoridation of public water supplies, there are both scientific and politico-legal dif- ferences. The biologicals are generally subject to prescription drug-like regulations in their development, use, surveillance, and other con- trol. Other community preventives are not al- ways deemed comparable medical or health agents. Vaccines are basically designed to meet widescale public needs, known or anticipated, whereas other community health programs are often limited in scope, duration, and continuing application. But the most significant difference lies in the fact that fluoridation, pollution con- trols, and environmental prohibitions are im- posed, whereas most vaccinations are offered for voluntary acceptance. HUMAN EXPERIMENTATION Scientific aspect. Are the rules now generally accepted for human experimentation appropriate for the research studies, develop- ment, and use of vaccines? Certainly the es- American Arbitration Association. Mount Sinai School ofMedicine, New York, New York. III 1.12La sentials of prior basic laboratory and animal in- vestigation apply. So do the requirements for competent researchby qualified staff. Also, scientific reviewiI .hnlcal evaluation must be imposed on development, production, and distribution of the biologic product to assure potency, purity, safety, and effectiveness. These are the underlying, insistent conditions stipulated in all countries. EtLical aspect. Are the medico4egal and ethical requisites equiIy suitable? Biologics and vaccines for human usE must be conceived and carried through development by pre-clinical tests and then by trliks on individuals, just as pharmaceuticals and other medical and health products are. Ho*ever, despite sophisticated methods of scientfic investigation, complete safety is still to be attaned. For example, risks appear to be inherent with live antigens and the possbilities for adverse effects are potentially greater when entire communities are involved. The balance of benefits and risks is critical. Wlthout the preventive vaccines, the inevitable impact and course 'of disease would adversely affect many peope.' The use of a vaccine, on the other hand, mnitst not be potentially more dangerous than the probable infection and its consequences. The critical ethiclc issue is the basis on which biologicals and vaccine research on human being can bq undertaken under present codes of ethics. The essentials in all such codes are -voluntary participation based on informed consent of candidate subjects, preceded by re- view and approval of the proposed research in light of prior scientific work, acceptable methodology, and assurances of safety. The re- search must be wholly optional; an offer to a subject to participte thus can be accepted or rejected without jeopardy to the subject or society. The frec4ojv, p choose is an inherent and essential element of involving human sub- jects in medical resdiMch. As part of these mquisites, there must be an assessment of likelibedefit compared with the risks involved. The idtrent considerations of this equation, largely based on the Declaration of Helsinkd, issued in 1964 by the World Medi- cal Association and revised in 1975, distinguish between therapeutic, or "benefiting," clinical research and non-therapeutic, or "busic," non- clinical research. The former is associated with patient care and the latter with problem investi- gation, using a subject (or patient not directly involved) for study. Generally, where studies require children and other dependent individuals for whom con- sent must be given by another (parent, guardian), such consent will be acceptable only where there is benefit to the subject. Therapeu- tic research is more easily recognized as "bene- fiting," or in the interests of the subject, usual- ly a patient, in this regard. Thus, "Iconsented" and "consenting" child- ren and infants, mentally or emotionally limited individuals, confined persons, and others deemed incapable of understanding and giving personal assent would be eligible for "therapeutic" research but perhaps only for such research. Such classes are among those often most likely to profit from immunization; but there can be no assurance of their direct benefit. In considering certain types of fetal re- search, the National Commission on Protection of Human Subjects recogized as "beneficial" research studies performed on those "at nrsk" but not necessarily directly benefited. Thus, the research leading to the vaccine for prevention of Rh-isoimmunization disease was categorized as "beneficial" (in considering research on live fetuses) since "all significant research on the fetus was conducted on mothers and fetuses at risk for the disease." The benefit compared to the risk established the beneficial nature of the studies(3). COMMUNITY ENTERPRISE Important to our review is the concept of community research as a recognized and identi- fiable endeavor. In that such research involves different objectives, methods, and outcomes there is a need for a complementary ethical foundation stressing societal as well as indivi- dual needs and benefits. There are many 112 Biolosical Rearch fof the Communty: Lega and Ethical Pespectives examples of essentially preventive research and health action directed to the community: ef- forts to stop the spread of disease, to conserve resources needed for healthy living, to preserve the environmental balance, to remove or reduce pollution, to purify water supplies, or to insure sanitary conditions and facilities. Yet, ethical codes have not been designed specifically for such public health and com- mumnty research. They can, however, rea- sonably be construed to accommodate com- munity enterprise studies, as exemplified in the following proposed interpretation of the Decla- ration of Helsinki(4). ETHICAL ACCEPTANCE OF COMMUNITY BENEFIT RESEARCH The Declaration of lHelsinki of the World Medical Association is generally recognized as the foremost codification of essential ethical principles and guidelines for clinical research. It is the single international document most fre- quently cited for reference in human experi- mentation and serves as the basis for many national and local codes. The Declaration now enjoys world respect and national emulation. The Declaration, as amended in 1975, has therefore been chosen as the text to illustrate how current codifications may embrace com- munity research. Selected passages are quoted in italics, followed by the interpretation, and an explanation of the intent or implication in parentheses. Introduction. 7he purpose of biomedical re- search involving human subjects must be to im- prove diagnostic, therapeutic and prophylactic procedurs and the understanding of the aetio- logy and pathogenesis ofdisease. Among these purposes, research in which the public, consisting of communities and indivi- duals, is the principal beneficiary, should be identified for special guidance to doctors and other medical and health authorities. (This interpretation does not suggest special consideration to provide particular advantage but serves to alert doctors and health authori- ties [to whom the Declaration should also be addressed] to applicable guidance in this area). In the field of biomedical research a funda- mental distinction nust be recognized between medical research n which the aim is essentialy diagnostic or therapeutic for a patient, and medical research, the essential object of which is purely scientific and without direct diagnos- tic or therapeutic value to the person subjected to the research. Among the types of medical research con- sidered essentially diagnostic or therapeutic for a patient may be included research directed to the collective benefit of the community, com- prised of individuals whose current or likely future condition will be directly aided through participation as a member of a subject or con- trol group. (This interpretaion would place research on biologicals, certainly those aimed at actual or potential major community problems, in the category of clinical research [medical research combined with professional carel and establish preventive or prophylactic concem as therapeu- tic.) Special caution should be exercsed in the conduct of research wickh may affect the en- virnment, and the welfare of anmals used for research must be respected. In the caution expressed for the environ- ment, the condition of the community, in- cluding its people and their vulnerability to communicable diseases, shall be given special recognition. (With this interpretation, "environment" as a concept embraces a human community, and thus any special caution to be exercised would also include concern for studies and trials that would affect a human population group.) BDu priiple. 7he design and performance of each experimental procedure involving human subjects should be clearly formulsted in an expenmental protocol which should be transmitted to a specially appointed Indepen- dent comnmttee for consideration, comment, and guidance. 113 L L.dIrw Experimental e dums involving progres- sive trials in cine aily lager population groups and cou upe such as for preventive procedures or produts for the public, shall be specifically ewumintraw4 with reference at each stage to the impat on the communities which may be involmy cd4F such studies the commit- tee shall include c s ty repesentatives and public offlcials (at tosd for technical assit- ance). (This clarifk%a#o is intended to identify community snarch i adwance, reqig parti- cular reference to its impact (potential benefit, risk and condijtio, ,a the community and to insure that such resrwch will be properly re- viewed by all cEnerd interests, with neces sary technical advice.) Eey biomedica research project involving human subjects od be preceded by careful assessment of pmtctble risks in companson with foreseeabk. befits to the subject or to others Concerm forthf interests of the subjet must alwaysppeWl wer the interests ofscience and society. In the determination of risk-benefit relation- ships, the foreesoaetoelets for a community or group of i4tWlb intended as subjects shall include, arus other elements, the poten- tial benefit to numbas of people, potentially vulnerable en musa, to disa; the signifiance to each individual of economical prevention and treatment thro* eventual application on a community baWi9; and the possible detriment to each individual through delay in seeking the benefits of couunit research. Conicern for the semts of the subject shall include and be conrntint with the interests of each subject as a mn *er ofsociety, particular- ly the community for which the research is pro- posed. The interes of society, likewise, shall be construed to includ each of it, members. (This critical giterpretation seeks to bridge the dichotomy of i divi&Wa1 and societal in- terests and etaihex, within the risk-benefit framework, the cawept that the benefit for an indivdual, in cwr*0iring proposed community research, shall ass the gain derived as a mem- ber of the commsmity. The significance of this formulation of "individual interest" is that, as in other aspects of life in civilized societies, benefit to an individual and to individuals col- lectively is more often seen as the same, rather than as different. Moreover, to the extent that this interpretation may apply, research projects [and review] will be designed and conducted to encompass both sets of interests or at least to reduce any actual or apparent conflict.) In any research on human beins, each po- tential subject mut be adequately informed of the aims, methods, anticWated benflts and potential hzais of the study and the discon- fort it may entaiL He or she should be informe that he or she is at liberty to abstain from pri- (lpaton in the study and that he or she is free to wthdraw his or her consent to partcipation at any time. The doctor should then obtain the subject's freeiy-grven informe consent, prefer- bly in writing Informed consent, based on full notice and explanation, shll be obtained individually with respect to each potential subject or representa- tive, but studies involving large groups, entire communities, or mass trials may appropriately allow for full explanation and information on a group basis by the doctors, their agents, or pub- lic health representatives as approved by the in- dependent committee. (This interpretation recognizes the reality of vaccine research studies at later stages; it main- tans individual consent but does not require personal doctor-patient. or investigator-subject exchange, provided there are other approved ar- rangements.) When obtining informed consentfor the re search project, the doctor should be particular- ly cautious if the subject is in a dependent re- lationship to him or her or may consent under uress. In that case the informed consent should be obtained by a doctor who Is not engaged in the lnvestgatiom and who is com- pletely independent of this official relationhp. In considering dependent relationships or the possbility of duress, the possibility of social coercion or public requirement shall be recognized and appropriate independent discus- sion or advocacy shall be provided. Biological Resrch for the Community: Lea and Ethical Perspectives 115 (This interpretation appreciates that public or professional authonty as much as the depen- dent relationship may prove coercive; but, through independent explanation or representa- tion, this potential duress may be overcome. At the same time, effective health education may fairly present the public interest.) (Ptopowd). Research enterprises in which the community or the public is deemed to be the principal beneficiary shall provide for com- pensation (monetary and medical) to or on be- half of subjects injured or disabled in conse- quence of participation, without requiring proof offault or neglect in the production, dis- tribution, or application of the substances used or in the pre-clinical investigation or approval. Such compensation nmy be in accordance with national legislation or agreement made for the research, as approved by the committee respon- sible for consideration, comment and guidance. (This provision for compensation is recom- mended for community enterprise research on the ground that the public benefit should be reflected in direct public responsibility. Inclu- sion of such a provision may encourage the principle of no-fault compensation for other categories of research with human beings.) SUMMARY The revised Declaration of Helsinki has been selectively amplified and interpreted to accom- modate research intended to benefit each com- munity as well as the general public. The Declaration would be modified in only one re- spect, i.e., addition of a provision for compen- sation of injured research subjects under legisla- tion or agreement. Essentially, the explanations seek to include community research as clinical, wherever possi- ble, and to recognize that individual and socie- tal benefit or interest are not necessanly in con- flict. Thus, individual benefit is recognized as capable of being supported by appropriate demonstration of community benefit in the protocol and to a review committee. With such acceptance, the standards for Medical Research combined with Professional Care (clinical re- search) would apply. CONCLUSION Few scientific activities contribute as much to community health and well being as mass vaccination. Those who take part serve them- selves, their neighbors, and their associates. Campaigns of vaccination and the field trials which precede them require full legal support through appropriate public health law and regu- lation and should provide for compensation of those injured as participants. They also require appropnate ethical consideration in the adapta- tion of codes and guidance for human studies to permit all persons, including children and other dependents, to take part freely and intel- ligently. To this end, the direct and active commit- ment of the public through well established community service and voluntary health groups and worker and employer organizations should be sought. The professions and governmental authorities can and should direct their interest and efforts to gain such cooperation. References 1. Who Should Bear the Legal Risk m Public Health Campaigns? Medical World News, Sept. 1970, p. 28: Bad Omen for U.S. Vaccine Supplies-Legal Decisions are Exposing Firms to lncreasing Liability. Medical World News, Sept. 1975, p. 75. 2. Bnefs Filed in Reyes v. Wyeth Laboratories: No. 72-2251, U.S. Court of Appeals (5) in 1972. See also Polio Vaccine Damages Upheld Again-High Court Refuses to Hear Appeal: American Medical News, Jan. 5, 1975, p. 1- 3. U.S. Department of Health, Education, and Welfare- Protection of Human Subjects-Fetuses, Pregnant Women, and in vitro Fertilization.Federal Register, 45: (No 154) 33535, August 8, 1975. 4. Refshauge, W.: The Place for International Standards m Conducting Research on Humans, Presented at the Intarnational Conference on the Role of the Individual and the Community in the Research, Development, and Use of Bioogicals, Geneva, Switzerland, March 2-5, 1976 (pp 133- 139 in these proceedings).